Botulinum neurotoxin serotype A (BoNTA) is a highly toxic by-product of a naturally occurring, spore-forming anaerobic bacterium (Clostridium botulinum). BoNTA inhibits the release of acetylcholine from presynaptic nerve terminals at neuromuscular junctions, causing flaccid paralysis and leading to death by respiratory arrest. BoNTA also can be used in the treatment of various muscular dysfunctions and has been widely used as a cosmetic known as BOTOX® to diminish facial lines. BoNTA, however, is fatal when misused, and there are currently no chemical antidotes to BoNTA.
The crystal structure of holo BoNTA includes two polypeptide chains that are linked by a disulfide bond. The light chain (50 KDa) is a zinc endopeptidase that specifically cleaves neuronal proteins responsible for acetylcholine release. The heavy chain (100 KDa) mediates selective binding to neuronal cells via specific gangliosides and translocates the light chain into the cytosol after receptor-mediated endocytosis of the entire molecule. Of eight serotypes of BoNT, serotypes A, D and E are closely related, according to sequence analysis using ClustalW.